Essential role of sphingosine 1–phosphate receptor 2 in pathological angiogenesis of the mouse retina
Open Access
- 4 September 2007
- journal article
- Published by American Society for Clinical Investigation in Journal of Clinical Investigation
- Vol. 117 (9) , 2506-2516
- https://doi.org/10.1172/jci31123
Abstract
Sphingosine 1–phosphate (S1P), a multifunctional lipid mediator that signals via the S1P family of G protein–coupled receptors (S1PR), regulates vascular maturation, permeability, and angiogenesis. In this study, we explored the role of S1P 2 receptor (S1P2R) in normal vascularization and hypoxia-triggered pathological angiogenesis of the mouse retina. S1P2R is strongly induced in ECs during hypoxic stress. When neonatal mice were subjected to ischemia-driven retinopathy, pathologic neovascularization in the vitreous chamber was suppressed in S1p2–/– mice concomitant with reduction in endothelial gaps and inflammatory cell infiltration. In addition, EC patterning and normal revascularization into the avascular zones of the retina were augmented. Reduced expression of the proinflammatory enzyme cyclooxygenase-2 (COX-2) and increased expression of eNOS were observed in the S1p2–/– mouse retina. S1P2R activation in ECs induced COX-2 expression and suppressed the expression of eNOS. These data identify the S1P2R-driven inflammatory process as an important molecular event in pathological retinal angiogenesis. We propose that antagonism of the S1P2R may be a novel therapeutic approach for the prevention and/or treatment of pathologic ocular neovascularization.Keywords
This publication has 65 references indexed in Scilit:
- Deafness and Stria Vascularis Defects in S1P2 Receptor-null MiceJournal of Biological Chemistry, 2007
- Notch expression patterns in the retina: An eye on receptor–ligand distribution during angiogenesisGene Expression Patterns, 2007
- Diabetes Alters Sphingolipid Metabolism in the RetinaDiabetes, 2006
- Myeloid progenitors differentiate into microglia and promote vascular repair in a model of ischemic retinopathyJournal of Clinical Investigation, 2006
- Pharmacologic Manipulation of Sphingosine Kinase in Retinal Endothelial Cells: Implications for Angiogenic Ocular DiseasesInvestigative Opthalmology & Visual Science, 2006
- Ex vivo pretreatment of bone marrow mononuclear cells with endothelial NO synthase enhancer AVE9488 enhances their functional activity for cell therapyProceedings of the National Academy of Sciences, 2006
- Extracellular export of sphingosine kinase-1a contributes to the vascular S1P gradientBiochemical Journal, 2006
- The Sphingosine-1-phosphate Receptors S1P1, S1P2, and S1P3 Function Coordinately during Embryonic AngiogenesisJournal of Biological Chemistry, 2004
- Glucocorticoid-Mediated Suppression of the Promoter Activity of the Cyclooxygenase-2 Gene Is Modulated by Expression of Its Receptor in Vascular Endothelial CellsBiochemical and Biophysical Research Communications, 1999
- Effects of the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors, atorvastatin and simvastatin, on the expression of endothelin-1 and endothelial nitric oxide synthase in vascular endothelial cells.Journal of Clinical Investigation, 1998